Live attenuated vaccines are considered among the most powerful tools for disease control and potentially disease eradication. Although vaccines have made a major contribution to public health, there are still significant deaths from diseases for which vaccines are not available. When vaccines are available, they may not be completely satisfactory in terms of safety, efficacy, and costs.
Attenuated bacteria that are unable to cause clinical diseases, but do trigger a self-limiting infection leading to the stimulation of protective immunity, represent an attractive method to prevent and/or treat infections. Because of their capacity for efficient mucosal antigen delivery, live attenuated Salmonella enterica serovar Typhimurim (S. Typhimurium) strains are considered good candidates for vaccine vectors. They have been used for expression of foreign antigens to induce mucosal, humoral, and cellular immune responses against both the attenuated carrier Salmonella and the expressed foreign protective antigen. S. Typhimurium gains access to internal lymphoid tissues by attaching to and invading through gut associated lymphoid tissues (GALT, including Peyer's patches) and stimulating a generalized secretory immune response. The ability of most attenuated vaccines to replicate in the host, results in the elicitation of strong and long-lasting immune responses, which mimic those stimulated by natural infections. A variety of attenuating mutations and antibiotic-free balanced-lethal plasmid stabilization systems has been developed for this purpose.
It is however essential to develop better, safer, and cheaper vaccines capable of promoting long-lasting protection.
Cancer is one of the leading killers in the US and around the world. The World Health organization (WHO) estimates that more than 20 million individuals are living with cancer and 84 million people will die of cancer between 2005 and 2015. The percentage of cancer-related deaths attributable just to diet and tobacco is as high as 60-70% worldwide. Moreover, more than 10 million people worldwide are expected to be diagnosed with cancer this year. In the US, almost 1.5 million people are diagnosed with cancer annually. It is the second leading cause of death after heart attacks and accounts for about 23% of total deaths. The five cancers that are associated with the highest number of deaths in the US are lung, breast, colorectal, prostate, and pancreatic. Cancer is also a major cause of morbidity and lost productivity costing billions of dollars to the US health care system. The cost due to both morbidity and premature mortality from cancer was estimated at $139.9 billion.
Cancer is a complex, multifactorial process. The disease is caused by both internal factors, such as genetics, hormones, and immune conditions and environmental/acquired factors, including environment, lifestyle and infections. Carcinogens and other risk factors affect chronic inflammation leading to tumorigenic pathway activation. Tumor cells are characterized by their low antigenicity and their high tumorigenicity, conditions that enable cancer cells to escape the immune system, allowing them to proliferate aggressively and metastasize to other tissues. Cancer patients often exhibit immunosuppression that primarily involves regulatory T cells and myeloid-derived suppressor cells.
Multiple approaches are used to treat different cancers including surgery, chemotherapy, biotherapy, radiotherapy, or a combination of these. Despite significant contributions to cancer treatment, the disease still causes high death rates. The limitations of these therapies are related to their toxicity, their ineffectiveness in targeting tumors, and their poor accessibility to tumor tissue. The fact that most tumors are characterized by their poorly vascularized hypoxic areas that limit the efficacy of radiation and chemotherapeutic drugs just magnifies the challenges in treatment. Hence, there is a need in the art for improved cancer treatments.